Nicotine has been used as an insecticide for many years (see, for example, D. E. H. Frear, "Chemistry of the Pesticides," 3rd Ed., D. Van Nostrand Co., New York, 1955). Although a number of natural as well as synthetic nicotinoids have been screened with regard to insecticidal activity, the vast majority are significantly less active than nicotine [see I. Yamamoto et al., Agr. biol. Chem. 32, 1341 (1968)]. The analogues of nicotine which have been tested involve either the alteration of the pyrrolidine moiety of the molecule, or the replacement of the pyridine ring with a substituted aromatic ring. Almost no work has been carried out with regard to examining the effects of pyridine substituents on insecticidal activity. F. Haglid et al. Acta. Chem. Scand., 21, 329, (1967) treated l-nicotine with methyl-lithium to yield at 5:1 mixture of 6-methylnicotine and 4-methylnicotine. The latter isomer was found to possess little or no nicotinic activity while 6-methylnicotine was identical in pharmacological activity to nicotine itself. This result indicates that the effect of a methyl group substituent ortho- to the pyrrolidine ring on the pyridine ring plays a major role in nicotinic activity in mammals; however the effect of such a methyl substituent on insecticidal activity has not been previously determined. The ultimate ability of an insecticide depends not only on its absolute insecticidal activity but also on its specificity; i.e., a compound with moderate insecticidal activity which is nontoxic to mammals would be desirable. As a consequence, the synthesis of ortho-alkylated nicotinoids and their evaluation as insecticides is of considerable interest. Haglid was unable to isolate 2-methylnicotine using the method referred to above; however, he presented evidence that indicates that a trace amount may have been present in the reaction mixture.
No routes to 2-substituted nicotinoids exist in the literature. Because of the substituent pattern involved and the well known resistance of pyridine toward Friedel-Crafts alkylation or acylation, precursors to such compounds are difficult to prepare. In reality, the regiospecific synthesis of polysubstituted pyridines is a continuing problem in modern heterocyclic chemistry.
The approach envisioned by the inventors for preparing 2-alkylnicotinoids involves the addition of an ortho substituent via the rearrangement of a monosubstituted pyridine. Although such reactions have not generally succeeded in pyridine chemistry, [see R. Paul and S. Tchelitcheff, Bull. Soc. Chem. Fr., 2134, (1968)], proper selection of the migrating moiety has made it possible to synthesize the desired 2-alkylnicotinoids. Preliminary results demonstrating the feasibility of these reactions have been published by the inventors in J. Org. Chem., 41, 2658, (1976). The paper describes a new synthetic process for the production of 2-alkyl-3-acylpyridines and 2-alkyl-3-formylpyridines via [2,3]-sigmatropic rearrangement of 1-cyanomethyl-1-[.alpha.-alkyl-2-picolyl)pyrrolidinium salts. The versatility of this procedure is evidenced by the fact that the .alpha.-cyanoamine initially obtained can be hydrolyzed to an aldehyde, reductively cleaved to an amine, or alkylated and hydrolyzed to a ketone.
Similar reactions involving homocyclic chemistry have been reported by Mander and Turner in J. Org. Chem., 38, 2915, (1972), wherein the [2,3]-sigmatropic rearrangement of ylids derived from allylic-N-cyanomethylpyrrolidinium salts followed by hydrolysis of the products afforded .beta., .gamma.,-unsaturated aldehydes.